RU2449782C2 - Vesicle applicable in medical product for external application to skin and medical product for external application to skin including vesicle - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical and cosmetic industry, particularly an agent applied to skin. A vesicle applied to skin containing α,ε-bis(γ-N-(C_10-30)acylglutamyl)lysine and/or its salt; ceramide and/or its derivative; and one or more ethers selected from glycerin ether of fatty acid, polyglycerin ether of fatty acid and glycerin ether of pyroglutamic acid taken in certain proportions. The therapeutic agent for external application to skin containing a certain amount of the vesicle.

EFFECT: vesicle and based therapeutic agent are stable, effectively encapsulates an active ingredient that allows it reaching true skin, effectively suppress transepidernal dehydration.

6 cl, 13 tbl, 8 ex

Description

Technical field

The present invention relates to a method for producing a dosage form for external use on the skin and especially to the use of a vesicle. The present invention also relates to a medicament for external use on skin obtained by a method for preparing a dosage form.

State of the art

Skin is an important tissue that separates the living organism and the environment. Accordingly, if the skin is damaged, this means that the protective barrier of a living organism is destroyed and the violation can cause serious damage to a living organism. In this regard, violations such as damage to the skin must be quickly eliminated. However, the function of the protective barrier of the skin becomes an obstacle for the penetration of drugs to eliminate the violation in the upper skin layers, especially in the dermis and, therefore, the condition that leads to mitigation of the violation is difficult. Accordingly, it is necessary to develop a method for the accurate delivery of drugs to the dermis.

Given the above conditions as a state of the art, various developments are being made to accelerate absorption through the skin. An example is a method comprising applying a “house of cards” structure or a mesh structure formed by an oil-based gel (Patent Document 1); a method comprising using a sound wave as a driving force for absorption through the skin (patent document 2); a method comprising using a solvent such as N-methyl-2-pyrrolidone (patent document 3); a method comprising using an ingredient that promotes absorption through the skin, such as lauryl sarcosine (patent document 4); and a method that allows a liposome or niosome, which is a sphere having a phospholipid bilayer structure, including an aqueous layer, to encapsulate the drug in the aqueous layer and mix the resulting preparation for external use on the skin (patent document 5). These methods contribute to the improvement far enough from satisfactory, and in many cases the above methods to accelerate absorption through the skin weaken the protective function of the skin itself.

On the other hand, as a method for preparing a dosage form using a vesicle, a method is known in which insoluble ingredients such as ceramide and phytosterol are purposefully mixed in an external medicine on the skin (patent document 6 and patent document 7). In addition, a method is also known in which an ingredient capable of reacting with water is encapsulated in a vesicle to stabilize the content of the vesicles in a water-based preparation (patent document 8). However, in these methods of using the vesicles, the surfactant for forming the vesicles is a cationic surfactant. Accordingly, its use, except as a detergent, is difficult and there have been many cases where the stability of the vesicle itself was problematic. As a result, there is a difficulty in applying the vesicles for a medicinal product for external use on the skin, which cannot be washed off.

On the other hand, a vesicle that contains α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine and / or its salt is not known at all.

It should be noted that the extract of Coptis (Ranunculaceae) , the extract of Citrus aurantium (Rutaceae) , the extract of red algae and the extract of Houttuynia (Saururaceae) have the ability to regulate the concentration gradient of calcium ions in the epidermis to enhance the protective function of the skin barrier (patent document 9). Rosmarinus officinalis extract is known to be capable of suppressing decomposition of elastin (patent document 10). Betula alba extract is known to be able to suppress the Mylard reaction (patent document 11). Extracts of Achillea and Ophiopogon are known to have the ability to lengthen the dendrite in melanocytes (patent document 12 and patent document 13). Syzygium aromaticum extract and triterpenes, such as oleanolic acid, betulinic acid and betulin, are known to have the ability to restore collagen bundles of dermis fibers (patent document 14 and patent document 15). Natural protein hydrolyzate is known to have the ability to inhibit elastase (patent document 16). It is known that panthetein sulfonate or its derivative and glycerritic acid or its derivative are capable of suppressing the allergic inflammation factor. It is known that hydroquinone or glycoside, esculin, esculletin, glabridine, methoxysalicylic acid, tranexamic acid or their derivatives have the ability to eliminate active oxygen to prevent oxidative stress occurring in the dermis (patent document 17).

[Patent Document 1] JP 2000-103722 A.

[Patent Document 2] JP H11-335271 A.

[Patent Document 3] JP H10-265379 A.

[Patent Document 4] JP H09-169637 A.

[Patent Document 5] JP 2004-143080 A.

[Patent Document 6] JP 2006-199635 A.

[Patent Document 7] JP 2006-199634 A.

[Patent Document 8] JP H09-40543 A.

[Patent Document 9] JP 2006-331294 A.

[Patent Document 10] JP 2005-132823 A.

[Patent Document 11] JP 2005-35911 A.

[Patent Document 12] JP 2003-113027 A.

[Patent Document 13] JP 2004-250354 A.

[Patent Document 14] JP 2002-29988 A.

[Patent Document 15] JP H09-143050 A.

[Patent Document 16] JP 2004-182687 A.

[Patent Document 17] JP 2000-344653 A.

Disclosure of the invention

The present invention can be successfully carried out, taking into account the above circumstances, and the object of the present invention provides a method that allows the active ingredient to reach the dermis to improve or maintain the skin environment.

In view of the above circumstances, the present inventors have thoroughly studied a method that allows the active ingredient to reach the dermis to improve or maintain the skin environment and as a result, they have found that the following vesicles have the ability to penetrate the dermis and perfectly encapsulate the active ingredient and, in addition, possess the ability to balance the skin environment in the vesicle vesicle itself, including: 1) α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine and / or its salt, 2) ceramide and / or its pro derivative, and 3) one or more esters selected from a glycerol fatty acid ester, a polyglycerol fatty acid ester, and pyroglutamic acid glycerol ester. Thus, the present invention has been completed, namely, the present invention is as follows.

(1) A vesicle, including:

1) α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine and / or its salt;

2) ceramide and / or its derivative; and

3) one or more esters selected from a glycerol fatty acid ester, a polyglycerol fatty acid ester, and pyroglutamic acid glycerol ester.

(2) The vesicle, in accordance with paragraph (1), in which the acyl group in α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine is a lauroyl group.

(3) A vesicle according to (1) or (2), wherein the ceramide or its derivative is a type 2 ceramide or a type 3 ceramide.

(4) A vesicle, in accordance with one of paragraphs (1) to (3), in which one or more esters is selected from a glycerol ester of a fatty acid, a polyglycerol ester of a fatty acid and a glycerol ester of pyroglutamic acid, and the glycerol ester of pyroglutamic acid is one or more esters selected from diglycerol monooleate, decaglycerol monoisostearate, decaglycerol pentaoleate and decaglycerol pentaisostearate.

(5) A vesicle, in accordance with one of paragraphs (1) to (3), further comprising one or more of the following active ingredients for improving or maintaining the skin environment: extract of Optis (Ranunculaceae) ; Citrus aurantium extract (Rutaceae) ; red algae extract; Houttuynia extract (Saururaceae); Rosmarinus officenalis extract (Lamiaceae); Betula alba extract (Betulaceae); Achillea extract (Asteraceae); Syzygium aromaticum extract (Myrtaceae); Centella extract (Umbelliferae); Engelhardtia chrysolepis extract (Juglandaceae); Ophiopogon extract (Liliaceae); natural protein hydrolyzate or its acylated product; oleanolic acid or its derivative; betullin; betullic acid or its derivative; panthein sulfonate or its derivative; glycerritic acid or its derivative; hydroquinone or its glycoside; esculin; esculletin; glabridin; methoxysalicylic acid; tranexamic acid or their derivatives; ascorbic acid or its derivatives; L-carnitine.

(6) A medicine for external application to the skin, comprising a vesicle in accordance with any one of paragraphs (1) to (5).

The best embodiment of the invention

(1) α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine, which is an essential ingredient in the vesicles of the present invention.

The drug for external application to the skin contains α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine as the main ingredient. α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine may also be present in free form or in salt form. Its salt can be used without any limitation, provided that the salt is any that can be used to obtain a medicine for external application to the skin. For example, preferred salt variants include: alkali metal salts such as sodium salt or potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic amine salts such as ammonium salt, triethanolamine salt and monoethanolamine salt; basic amino acid salts such as lysine salt and alginic acid salt. The acyl group is characterized by the inclusion of from 10 to 30 carbon atoms. The acyl group may be linear, branched or cyclic, or may be a saturated aliphatic group or an unsaturated aliphatic group. Specific examples of the acyl group include a decanoyl group, a lauroyl group, a myristoyl group, a stearoyl group, a behenoyl group, an isostearoyl group, an oleoyl group, and a linoleoyl group. Of these, a lauroyl group is most preferred. However, α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine contains two acyl groups, and the two acyl groups may be the same or different from each other. α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine can be obtained, for example, by the following procedure, namely, the procedure involves the interaction of glutamic acid with a carboxylic acid chloride in the presence of alkali, such as triethylamine to form resulting in N-acylglutamic acid and further condensation of N-acylglutamic acid in the presence of lysine and a peptide synthesis reagent such as DCC in a 2: 1 molar ratio. The reaction product thus obtained can be purified on a silica gel column or the like. The silica gel column elution solvent may preferably be a chloroform-methanol mixture. The structure of α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine is shown in formula 1.

Formula 1 (however, in the formula R ₁ and R ₂ each independently represents acyl group having from 10 to 30 carbon atoms).

α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine can be obtained and used in accordance with the above method. However, currently there is a commercially available α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine and a commercially available product can be purchased and used. The commercially available product described above may preferably be provided by “Pellicer L-30” (manufactured by Asahi Kasei Corporation; α, ε-bis (γ-N-lauroylglutamyl) lysine). Thus, the obtained α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine has a property that facilitates the easy formation of a bilayer membrane and thus the formation of a vesicle having excellent stability with the remaining necessary ingredients, which will be described Further. A vesicle has physical properties close to the membrane structure of epidermal cells and, therefore, excellently increases skin permeability. In addition to this, the vesicle has an excellent function of binding the active ingredient between the lipid bilayer of the membranes. This is due to the amphiphilic property of the lipid bilayer membranes themselves. In addition, in order to exhibit such a function, the vesicle contains one or more selected from α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine per total number of vesicles, taking into account the total number of vesicles, preferably 1 wt.% or more preferably 5% as the lower limit of the content and preferably 50 wt.% and most preferably 10 wt.% as the upper limit of the content. This is because there are cases where a stable vesicle may not form even when the amount of the above ingredients is too large or too small.

(2) Ceramide and its derivative, which are the natural ingredients of the vesicles of the present invention.

The vesicle of the present invention is characterized by the content of ceramide and its derivative (in this document, sometimes collectively referred to as "ceramides"). It is known that there are seven main types of ceramides, including from type 1 to type 7 (represented by the following formulas 2-7), and each of them can be used. Among them, type 2 is particularly preferred, and N-stearoyldihydroxy sphingosine is particularly preferred. These ceramides are commercially available and such commercially available products can be purchased and used. Examples of commercially available products include: “Ceramide I” (manufactured by Cosmo-Farm), containing N- (27-octadecanoyloxyheptacosanoyl) phytosphingosine, which is an ingredient of type 1; "Ceramide TIC-001" (manufactured by Takasago International Corporation) containing N-stearoyl-dihydroxy-sphingosine, which is an ingredient of type 2; "Ceramide III" (manufactured by Cosmo-Farm) containing N-stearoyl-phytosphingosine, which is an ingredient of type 3; "Ceramide IIIA" (manufactured by Cosmo-Farm) containing N-linoleoyl-phytosphingosine, which is an ingredient of type 3; "Ceramide IIIB" (manufactured by Cosmo-Farm) containing N-oleoyl-phytosphingosine, which is an ingredient of type 3; and Ceramide IV (manufactured by Cosmo-Farm), containing N-2-hydroxystearoyl-phytosphingosine, which is an ingredient of type 6. Ceramides may be contained singly or in combination of two or more. In the vesicle of the present invention, those ingredients which have the ability to enhance the structure of the vesicles are formed by α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine. In order to exhibit such an effect, the vesicle contains ceramides in an amount relative to the total amount of the vesicle, preferably 1 wt.% Or most preferably 5 wt.% As a lower limit and preferably 50 wt.% Or most preferably 10 wt.% As upper limit content. If the amount of ingredient is too large, then in some cases the above effect may not occur. In addition, the total weight ratio of ceramides to the total weight of α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine is preferably from 2: 1 to 1:50 and most preferably from 1: 1 to 1: 5 .

Ceramide Type 1

(R ₁ represents an alkyl group or an alkenyl group, and R ₂ represents a linoleoyloxyalkyl group. The number of carbon atoms in the alkyl group or alkenyl group R _{1 is} usually in the range of 15 to 18, and the number of carbon atoms in the linoleoyloxyalkyl group R _{2 is} usually in the range from 45 to 50).

Ceramide Type 2

(Each of R ₁ and R ₂ independently of each other represents an alkyl group or an alkenyl group. The number of carbon atoms in an alkyl group or an alkenyl group represented by R ₁ or R ₂ is usually in the range of 15 to 23).

Ceramide Type 3

(Each of R ₁ and R ₂ independently of each other represents an alkyl group. The number of carbon atoms in the alkyl group represented by R ₁ or R ₂ is usually in the range from 15 to 23).

Ceramide Type 4

(R ₁ represents an alkyl group and R ₂ represents a linoleoyloxyalkyl group. The number of carbon atoms in the alkyl group represented by R ₁ is usually in the range of 15 to 23, and the number of carbon atoms in the linoleoyloxyalkyl group of R _{2 is} usually in the range of 45 to 50).

Ceramide Type 5

(Each of R ₁ and R ₂ independently of each other represents an alkyl group. The number of carbon atoms in the alkyl group represented by R ₁ or R ₂ is usually in the range from 15 to 23).

Ceramide Type 6

(Each of R ₁ and R ₂ independently of each other represents an alkyl group, and R ₃ represents a hydrogen atom or an alkyl group. The number of carbon atoms in the alkyl group represented by R ₁ or R ₂ is usually in the range from 15 to 22 )

Ceramide Type 7

(Each of R ₁ and R ₂ independently of each other represents an alkyl group. The number of carbon atoms in the alkyl group represented by R ₁ or R ₂ is usually in the range from 15 to 22).

Ceramide derivatives, ceramide analogues or the like, such as sphingosine, sphingomyelin, sphingosylphosphorylcholine, and those described, for example, in JP S64-228048 A, JP S63-216812 A, JP S63-227513 A, JP S64-29347 A, JP S64-31752 A and JP H8-319263 A are preferred examples. Particularly, examples of ceramide derivatives can preferably be represented by ingredients of the following formula 8 and ingredients of the following formula 9.

(but, in the formula, R ₁ represents a hydrocarbon group having from 10 to 26 carbon atoms, R ₂ represents a hydrocarbon group having from 9 to 25 carbon atoms, and X represents the group - (CH ₂ ) n-, in which n has a value from 2 to 6).

(In the formula, each of R ₁ 'and R ₂ ' independently of each other represents a hydrocarbon group having from 1 to 40 carbon atoms that can be hydroxylated, R ₃ represents a linear or branched alkylene group having from 1 to 6 atoms carbon or a single bond, and R ₄ represents a hydrogen atom, a linear or branched alkoxy group having from 1 to 12 carbon atoms or a 2,3-dihydroxypropyl group. However, R ₄ represents a hydrogen atom when R ₃ represents a single bond) .

The ingredient represented by formula 8 or 9 can be obtained by the usual method in accordance with the contexts of the above patent documents.

(3) Glycerol fatty acid ester, polyglycerol fatty acid ester and pyroglutamic acid glycerol ester, which are the natural vesicle ingredients of the present invention.

The vesicle of the present invention contains, as natural ingredients, one or more ingredients selected from polyglycerol fatty acid ester and pyroglutamic acid glycerol ester.

Preferred examples of fatty acid residues of the glycerol fatty acid ester include lauric acid residue, myristic acid residue, palmitic acid residue, stearic acid residue, behenic acid residue, isostearic acid residue, oleic acid residue, linoleic acid residue, and linolenic acid residue and oleic acid residue , a stearic acid residue and an isostearic acid residue are particularly preferred.

In addition, the degree of polymerization of glycerol in the polyglycerol of the polyglycerol fatty acid ester is preferably from 2 to 20 and most preferably from 2 to 10. In addition, preferred examples of fatty acid residues include lauric acid residue, myristic acid residue, palmitic acid residue, stearic acid residue , the behenic acid residue, the isostearic acid residue, the oleic acid residue, the linoleic acid residue, and the linolenic acid residue and the oleic acid residue, the remainder ox stearic acid and an isostearic acid residue are particularly preferred. In the polyglycerol fatty acid ester described above, it is preferable that the number of fatty acid residues per molecule is greater than the number of free hydroxyl groups. Examples of such specific options are mono (di) glycerol ester of oleic acid, mono (di) glycerol ester of lauric acid, triglycerol ester of distearic acid, triglycerol ester of diisostearic acid, three (penta) glyceric ester of lauric acid, three (penta glyceric ester of lauric acid , three (penta) glycerin ester of oleic acid, three (penta) glycerol ester of isostearic acid, tetra (hepta) glyceric ester of lauric acid, tetra (hepta) glycerol ester of stearic acid, tetra (hept a) glycerol ester of oleic acid, tetra (hepta) glycerol ester of isostearic acid, penta (deca) glyceric ester of lauric acid, penta (deca) glyceric ester of stearic acid, penta (deca) glyceric ester of oleic acid, and penta (deca) glyceric ester isostearic acid is particularly preferred.

Examples of ingredients that have the same property as polyglycerol fatty acid ester include pyroglutamic acid glycerol esters such as pyroglutamine-stearic acid glycerol ester and pyroglutamine-oleic acid glycerol ester. These ingredients can be used in the vesicle of the present invention.

The aforementioned ceramides and α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine can form a stable vesicle only in the presence of the above one or more selected from glycerol fatty acid ester and pyroglutamine fatty acid ester. In order to obtain a stable vesicle, it is preferable that the total amount of one or more esters selected from glycerol fatty acid ester, polyglycerol fatty acid ester and pyroglutamine fatty acid ester with respect to the total number of vesicles preferably ranges from 5 to 30 wt.% And most preferably from 10 to 25 wt.%. In addition, the ratio of the total mass of glycerol fatty acid ester, polyglycerol fatty acid ester and pyroglutamine fatty acid ester to the total mass of α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine was preferably from 5: 1 to 1 : 1 and most preferably from 4: 1 to 2: 1. The interaction between the two elements leads to the ordering of the lipid bilayer of the membrane. Thus, ordered bilayer membranes can retain the active ingredient within themselves. In addition, this compatibility between the outer wall of the bilayer membrane and the cellular stratum corneum of the skin gives the vesicle excellent permeability in the stratum corneum. In addition, both ceramides and α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine exhibit a preferred function with respect to the dermis and, therefore, even when the vesicle does not contain the aforementioned active ingredient exhibiting an excellent effect improving or maintaining the skin.

The vesicle of the present invention may be a vesicle that contains one or more active ingredients to improve or maintain the skin, depending on its purpose.

The phrase “improving or maintaining the skin,” in particular, covers the following: enhancing the function of the skin barrier; blocking the breakdown of elastin; blocking the Mailard reaction or correcting the heterogeneity of the Mailard reaction; blocking the extension of dendrite in melanocyte; restoration of a collagen bundle of dermis fibers; elastase inhibition; blocking the inflammatory factor; etching of active oxygen and the like.

Specific examples of the above-mentioned active ingredients include, for example, Soptis (Ranunculaceae) extract, Citrus aurantium (Rutaceae), an extract of red algae (Ralmaria), Houttuynia (Saururaceae) extract, Rosmarinus officinalis extract, Betula alba, extracts of Achillea millefolium, Syzygium extract ( Myrtaceae), Hypericum extract (Clusiaceae), such as Hypericum perforatum, Centella extract (Apiaceae), Engelhardtia chrysolepis extract (Juglandaceae), Ophiopogon extract (Liliaceae), natural protein hydrolysates or their acylated hydrolysates, oleanolic acid and e derivatives betullin, betullinovaya acid or a derivative thereof, pantetheine sulfonic acid or its derivatives, glitserritinovaya acid or its derivatives; hydroquinone or its glycoside; esculin; esculletin; glabridin; methoxysalicylic acid; tranexamic acid or their derivatives; ascorbic acid or its derivatives; L-carnitine.

Сoptis (Ranunculaceae) extract, Citrus aurantium (Rutaceae) extract, red algae extract, Houttuynia (Saururaceae) extract have the ability to adjust the concentration gradient of calcium ions in the epidermis to enhance the protective function of the skin barrier. Rosmarinus officinalis extract has the ability to suppress the decomposition of elastin, Betula alba extract has the ability to suppress the Mailard reaction. The extracts of Achillea and Ophiopogon have the ability to lengthen the dendrite in melanocytes. Syzygium aromaticum extract, eugenol and triterpenes such as oleanolic acid, betulinic acid and betulin have the ability to restore collagen bundles of dermis fibers. Natural protein hydrolyzate has the ability to inhibit elastase. Panthein sulfonate or its derivative and glycerritic acid or its derivative have the ability to suppress the allergic inflammation factor. Hydroquinone or glycoside, esculin, esculletin, glabridine, methoxysalicylic acid, tranexamic acid or their derivatives have the ability to eliminate active oxygen to prevent oxidative stress occurring in the dermis. The content of this ingredient in the vesicle of the present invention can be set to some extent equal to the amount necessary to manifest the above properties and, for example, the content of each active ingredient can be preferably from 0.1 to 30 wt.% And most preferably from 1 to 10 wt.% in relation to the total weight of the vesicles.

The vesicle of the present invention may contain an arbitrary ingredient that is commonly used in a vesicle and drug for external use on the skin in addition to the aforementioned natural ingredients and preferred ingredients. Such suitable compounds may preferably include polyvalent alcohols, such as glycerin, diglycerin, dipropylene glycol, 1,3-butanediol, 1,2-pentanediol, isoprenglycol, 1,2-hexanediol, 1,2-octanediol and polyethylene glycol; cyclic alcohols such as cholesterol, campesterol, sitosterol, stigmasterol; phospholipids such as lecithin, hydrogenated lecithin, hydroxylated lecithin, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine and phosphatidylglycerol; fatty acids such as oleic acid, capric acid, caprylic acid and stearic acid; higher alcohols, such as cetanol, stearyl alcohol and oleyl alcohol; methyl paraben and ethyl paraben. Among them, particularly preferred options include cyclic alcohols, in particular phytosterols, such as campesterol, sitosterol and stigmasterol; polyvalent alcohol and even glycerin. The phytosterol content is preferably 2: 1 to 1: 2 with respect to α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine, and the polyvalent alcohol content, which is a natural ingredient, is preferably 5 to 15 times more with respect to α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine. The vesicle of the present invention can be used to obtain the dispersion composition of the vesicles by treating the natural ingredients in the main way, the preferred ingredients and arbitrary ingredients.

(4) Drug for external application to the skin

A topical skin preparation of the present invention is characterized by the content of the aforementioned vesicle. Since the medicine for external application to the skin contains a vesicle, the active ingredient is delivered to the dermis and, in addition, α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine itself, which is an integral part of the vesicle, acts on dermis, improving the properties of the dermis. In order to exhibit these properties, the vesicle content is preferably from 0.1 to 10 wt.% And most preferably from 0.5 to 5 wt.% With respect to the total weight of the drug for external use on the skin. If the content is too low, then sufficient amounts of α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine, ceramides and active ingredients cannot reach the dermis to exhibit properties, while if the content is too high , the effective level reaches the limit and, as a result, the degree of freedom for the drug is weakened.

The external skin medicine of the present invention can be applied without any special limitation for as long as it is usually applied to the external skin. Preferred examples of a medicament for external application to the skin include cosmetics containing general-purpose substances, skin medicaments for external use, and dermatological products suitable for external use. Among them, cosmetics are particularly preferred. This is due to the fact that cosmetics achieve the desired access to the skin and contain many active ingredients with low access to the skin. Preferred examples of cosmetics include lotions, milk lotions, cosmetic essential oils, cosmetic remover formulations, and cleansing cosmetics. In addition, the dosage forms of these cosmetics are not particularly limited since they have long been known in the field of cosmetics and can preferably be used in the form of lotions, oil-in-water emulsions, water-in-oil emulsions, complex emulsions of emulsifiable dosage forms and the like.

A topical skin preparation of the present invention may contain additional ingredients commonly used as natural ingredients for a topical skin preparation. Preferred examples of such additional ingredients include: oils / waxes, such as macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, coconut oil, palm oil, cottonseed oil, jojoba oil , ripened coconut oil, reconstituted oil, sumac oil (vegetable wax), reconstituted castor oil, beeswax, candelilla wax, carnauba wax, ibot wax, lanolin, reconstituted lanolin, hard lanolin, wax zhoba; hydrocarbons, such as liquid paraffin, squalane, pristan, ozokerite, paraffin, ceresin, petroleum jelly and microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid and undecylenic acid; higher alcohols such as cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol and cetostearyl alcohol; synthetic ester oils such as tsetilizotsianat, isopropyl myristate, geksildetsilizostearat, isopropyl myristate, geksildetsilizostearat, diisopropyl adipate, di-2-ethylhexylsebacate, diisostearyl malate, ethylene glycol di-2-etilgeksonat, neo-pentilglikoldikaprat, glyceryl di-2-heptylundecanoate, glyceryl tri-2-ethylhexanoate trimethylolpropane tri-2-ethylhexanoate, tri-methylolpropane triisostearate and pentaerythritol tetra-2-ethylhexanoate; chain polysiloxanes, such as dimethylpolysiloxane, methylphenylpolysiloxane and diphenylpolysiloxane; cyclic polysiloxanes such as octamethylcyclotetra-siloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexane-siloxane; modified polysiloxanes, such as amine-modified polysiloxane, polyester-modified polysiloxane, alkyl-modified polysiloxane and fluorine-modified polysiloxane; oil agents, such as silicon oil; anionic surfactants such as synthetic fatty acid soaps (such as sodium laureate and sodium palmitate), sodium lauryl sulfate and triethanolamine alkyl sulfate ester; cationic surfactants such as stearyl chloride trimethyl ammonium chloride, benzalkonium chloride and laurylamine oxide; amphoteric surfactants such as imidazoline-based amphoteric surfactants (such as 2-cocoyl-2-imidazoline hydroxide-1-carboxyethyl oxide sodium salt), betaine-based surfactants (such as alkyl betaine, amide betaine and sulfobetaine) and acylmethyl taurine; nonionic surfactants, such as sorbitol fatty acid esters (such as sorbitan monostearate and sesquioleate sorbitan), glycerol fatty acid esters (such as glycerol monostearate), propylene glycol fatty acid esters (such as propylene glycol monostearate), reduced derivatives of castor oil, glycerol alkyl ether, POE-sorbitan fatty acid esters (such as POE-sorbitan monooleate and polyoxyethylene sorbitan monostearate), POE-sorbitol fatty acid esters (such as POE-sorbitol monolau rat), POE-glycerol fatty acid esters (such as POE-glycerol monoisostearate), POE fatty acid esters (such as polyethylene glycol monooleate and POE distearate), POE-alkyl esters (such as POE2-octyldodecyl ether), POE- alkylphenyl ethers (such as POE nonylphenyl ether), representatives of surfactants, POE / POP alkyl ethers such as POE / POP2-decyl tetradecyl ether), emulsifiers, POE castor oil / reduced castor oil derivatives (such as like poe-castor oil and restore ennye derivatives, POE-castor oil), fatty acid esters of sucrose and alkyl glycoside; polyvalent alcohols, such as polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerin, isoprenglycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol and 1,2-octanediol; moisturizing ingredients such as pyrrolidone sodium carboxylate, lactate and sodium lactate; fine particles such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, silicon anhydride (silica gel), alumina and barium sulfate, the surfaces of which can be treated; inorganic pigments such as red iron oxide, yellow iron oxide pigment, black iron oxide pigment, cobalt oxide, ultramarine blue pigment, Prussian blue, titanium oxide and zinc oxide, the surfaces of which can be treated; pearlescent agents such as titanium mica, fish scales and bismuth oxychloride, the surfaces of which can be treated; organic dyes such as red No. 202, red No. 228, red No. 226, yellow No. 4, blue No. 404, yellow No. 5, red No. 5, red No. 505, red No. 230, red No. 223, orange No. 201, red No. 213, yellow No. 204, yellow No. 203, blue No. 1, green No. 201, purple No. 201 and red No. 204, which may be lacquered; fine organic particles such as polyethylene powder, polymethyl methacrylate, polyamide powder and polyorganosiloxane elastomer; p-aminobenzoate-based ultraviolet absorbent; anthranilate-based ultraviolet absorbent; cinnamate-based ultraviolet absorbent; benzophenone-based ultraviolet absorbent; sucrose-based ultraviolet absorbent; ultraviolet absorbents such as 2- (2'-hydroxy-5'-tert-octylphenyl) benzotriazole and 4-methoxy-4'-tert-butyldibenzoylmethane; lower alcohols such as ethanol and isopropanol; vitamins such as vitamin A or its derivatives; B vitamins such as vitamin B ₆ tripalmitate, vitamin B ₆ dioctanoate, vitamin B ₂ or its derivatives, vitamin B ₁₂ and vitamin B ₁₅ or its derivatives; vitamins of group E such as α-tocopherol, β-tocopherol, γ-tocopherol and vitamin E acetate, vitamins of group D, vitamin H, pantothenic acid, pantetin, pyrroloquinolinequinone; and antibacterial agents such as phenoxyethanol.

A topical skin preparation of the present invention can be prepared by treating a natural ingredient and an additional ingredient in a conventional manner.

Hereinafter, the present invention is described in specific details by examples, but it goes without saying that the present invention is not limited to these examples.

Example 1

The liquid vesicular dispersion 1 of the present invention was obtained in accordance with the following technology, namely, ingredients A and ingredients B were heated to 70 ° C while being homogeneously dissolved and ingredients B were gradually added to ingredients A with stirring, resulting in a liquid vesicular dispersion. A part of the liquid vesicular dispersion was separated and weighed, and then centrifuged, the supernatant was removed, the product was washed twice with water, dried and weighed, and the mass content of the vesicle in the liquid vesicular dispersion was calculated, which amounted to 9.3 wt.%. In addition, in the same process, the following was processed in a similar manner: Comparative Sample 1, in which the lecithin was replaced with “Rellicer L-30”; comparative sample 2, in which the "Rellicer L-30" was replaced by "Ceramide TIC-001"; and comparative sample 3, in which the polyoxyethylene (2) oleate was replaced with diglycerin monooleate. As a result of observation using a polarizing microscope, polarized light was not identified in any of the comparative samples 1, 2 and 3 and, therefore, it was found that comparative sample 1, comparative sample 2 and comparative sample 3 did not form a vesicular dispersion system.

Table 1 Ingredients Mass% BUT Ceramide TIC-001 one Sitosterol one "Rellicer L-30" one Diglycerin monooleate 3 Glycerol 10 AT Phenoxyethanol 0.5 Water 83.5 Total one hundred

Example 2

Reference example 1

The whole Palmaria palmat plant was dried and then weighed 100 g of the dried product. Added 2 l of water, the product was gradually heated to 60 ° C, the temperature was maintained for 3 hours, and then the product was selected and allowed to cool at room temperature. After cooling, insoluble impurities were removed by filtration, and the filtrate was lyophilized in order to obtain 1 Ralmaria extract.

The above extract 1 of Ralmaria was used to obtain a liquid vesicular dispersion 2 in the same manner as in example 1. In addition, as in example 1, the following was processed in the same way: comparative sample 4, in which the lecithin was replaced by “Rellicer L- thirty"; comparative sample 5, in which the "Rellicer L-30" was replaced by "Ceramide TIC-001"; and comparative sample 6, in which the polyoxyethylene (2) oleate was replaced with diglycerol monooleate. As a result of observation using a polarizing microscope, polarized light was not identified in any of the comparative samples 4, 5 and 6 and, therefore, it was found that comparative sample 4, comparative sample 5 and comparative sample 6 did not form a vesicular dispersion system. In addition, the mass of the vesicles contained in the liquid vesicular dispersion 2 was 9.8 wt.%.

table 2 Ingredients Mass% BUT Ceramide TIC-001 one Sitosterol one "Rellicer L-30" one Diglycerin monooleate 3 10% aqueous solution of Palmaria extract 1 one Glycerol 10 AT Phenoxyethanol 0.5 Water 82.5 Total one hundred

Test case 1

Liquid vesicular dispersion 1, liquid vesicular dispersion 2, comparative sample 4, comparative sample 5 and comparative sample 6 were used as a sample. The skin was pretreated and corked with a 1% aqueous solution of lauryl sulfate for 24 hours to enhance transepidermal (through the skin) moisture loss (TEPV) and was treated and capped by the sample for 6 hours and 30 minutes after removing the dressing, TEPV was determined using a Tevameter (manufactured by Integral Corporation). It should be noted that water was used as a control. Table 3 shows the results. It has been found that liquid vesicular dispersion has an additional excellent TEPV suppression effect. This is possibly due to the fact that 1 Palmaria extract, which is the active ingredient, strengthens the vesicle itself. In addition, it was found that the “Rellicer L-30” itself has the ability to suppress TEPV.

Table 3 Samples TEPV The control 28 Liquid vesicular dispersion 1 21 Liquid vesicular dispersion 2 13 Reference Example 4 24 Reference Example 5 eighteen Comparative Sample 6 19

Example 3

Comparative Example 2

To 500 g of ground parts of the rhizome of Сoptis japonica belonging to Сoptis (Ranunculaceae) , add 3 l of a 50% aqueous solution of ethanol, the mixture is heated with stirring and heated in a flask under reflux for 3 hours. After cooling to room temperature, insoluble impurities are removed by filtration. The resulting product was concentrated in vacuo and 1 L of water and 1 L of ethyl acetate were added to conduct liquid extraction of the residue. The ethyl acetate layer was separated and washed twice with 500 ml of water, followed by drying with anhydrous sodium sulfate. After that, the resulting product was concentrated in vacuo to remove the solvent, and as a result extract 1 of Coptis japonica was obtained.

Comparative Example 3

A similar treatment was carried out except that instead of parts of the rhizome of Сoptis japonica belonging to Сoptis (Ranunculaceae), the fruit peel of Citrus aurantium (Rutaceae) was used in order to obtain Citrus aurantium extract 1 .

Comparative Example 4

A similar treatment was carried out except that the aerial part of Houttuynia cordata (Saururaceae) was used instead of parts of the rhizome of Coptis japonica belonging to Coptis (Ranunculaceae) in order to obtain extract 1 of Houttuynia cordata.

Comparative Example 5

A similar treatment was performed except that instead of parts of the rhizome of Coptis japonica belonging to Coptis (Ranunculaceae), the leaves of Rosmarinus officinalis (Lamiaceae) were used to obtain Rosmarinus officinalis extract 1 .

Comparative Example 6

A similar treatment was carried out except that instead of parts of the rhizome of Сoptis japonica belonging to Сoptis (Ranunculaceae), the bark of Betula alba (Betulaceae) was used in order to obtain Betula alba extract 1 .

Comparative Example 7

A similar treatment was carried out except that instead of parts of the rhizome of Coptis japonica belonging to Coptis (Ranunculaceae), the aerial part of Achillea millefolium (Compositae) was used in order to obtain Achillea millefolium extract 1 .

Comparative Example 8

A similar treatment was carried out except that instead of parts of the rhizome of Сoptis japonica belonging to Сoptis (Ranunculaceae), the aerial part of Centella asiatica (Apiaceae) was used to obtain Centella asiatica extract 1 .

Comparative Example 9

A similar treatment was performed except that instead of parts of the rhizome of Coptis japonica belonging to Coptis (Ranunculaceae), foliage of Engelgardtia chrysolepis (Juglandaceae) was used in order to obtain Engelgardtia chrysolepis extract 1 .

Comparative Example 10

A similar treatment was carried out except that instead of parts of the rhizome of Coptis japonica belonging to Soptis (Ranunculaceae), rhizomes of Ophiopogon japonicus (Liliaceae) were used and a 50% aqueous solution of ethanol was used instead of ethanol to obtain Ophiopogon japonicas extract 1 .

The liquid vesicular dispersion 1 in which the vesicle of the present invention was dispersed was obtained in a similar manner as in Example 2 in accordance with the following composition.

Table 4 Ingredients Mass% BUT Ceramide TIC-001 one Sitosterol one "Rellicer L-30" one Diglycerin monooleate 3 The ingredients shown in table 5 0.1 Glycerol 10 AT Phenoxyethanol 0.5 Water 83,4 Total one hundred

Table 5 Liquid vesicular dispersions Ingredients Property 3 Extract 1 optis japonica Vesicular dispersed system four Citrus aurantium Extract 1 Vesicular dispersed system 5 Houttuynia cordata extract 1 Vesicular dispersed system 6 Rosmarinus officinalis Extract 1 Vesicular dispersed system 7 Extract 1 Betula alba Vesicular dispersed system 8 Achillea millefolium extract 1 Vesicular dispersed system 9 Extract 1 Centella asiatica Vesicular dispersed system 10 Engelgardtia chrysolepis Extract 1 Vesicular dispersed system eleven Ophiopogon japonicas Extract 1 Vesicular dispersed system 12 Eugenol Vesicular dispersed system 13 Oleanolic acid Vesicular dispersed system fourteen Oleanolic acid methyl ester Vesicular dispersed system fifteen Ascorbic Acid Glycoside Vesicular dispersed system 16 Soy Protein Hydrolyzate Vesicular dispersed system 17 Lauroil Silk Protein Hydrolyzate Vesicular dispersed system eighteen Arbutin Vesicular dispersed system 19 Panthein sulfonate Vesicular dispersed system twenty Glabridin Vesicular dispersed system 21 Esculletin Vesicular dispersed system 22 Stearyl Glycerol Vesicular dispersed system

Example 4

The same steps were carried out using various surfactants in the same manner as in Example 3.

Table 6 Ingredients Mass% BUT Ceramide TIC-001 one Sitosterol one "Rellicer L-30" one Surfactants shown in table 7 3 10% aqueous solution of Palmaria extract 1 one Glycerol 10 AT Phenoxyethanol 0.5 Water 82.5 Total one hundred

Table 7 Liquid vesicular dispersions Ingredients Property 23 Diglycerin monostearate Vesicular dispersed system 24 Diglycerin monoisostearate Vesicular dispersed system 25 Triglycerol Diisostearate Vesicular dispersed system 26 Pentaglycerol Trioleate Vesicular dispersed system 27 Decaglycerin Hexaoleate Vesicular dispersed system 28 Glycerol ester of pyroglutamic and oleic acid Vesicular dispersed system

Example 5

Liquid vesicular dispersion 29 was obtained in the same manner as in example 3 in accordance with the following composition. The formation of an emulsion in part of the vesicles was also observed.

Table 8 Ingredients Mass% BUT Ceramide TIC-001 one Sitosterol one "Rellicer L-30" one Decaglycerin Monostearate 3 10% aqueous solution of Palmaria extract 1 one Glycerol 10 AT Phenoxyethanol 0.5 Water 82.5 Total one hundred

Example 6

Liquid vesicular dispersion 30 was obtained in the same manner as in example 3 in accordance with the following composition. It was a vesicular dispersed system.

Table 9 Ingredients Mass% BUT Ceramide TIC-001 0.3 Sitosterol 0.3 "Rellicer L-30" one Decaglycerin Monostearate 3 10% aqueous solution of Palmaria extract 1 one 1,3-butanediol 10 Glycerol 10 AT Phenoxyethanol 0.5 Water 83.9 Total one hundred

Example 7

The same steps were carried out using different types of ceramides in the same manner as in Example 3.

Table 10 Ingredients Mass% BUT The ingredients shown in table 11 one Sitosterol one "Rellicer L-30" one Decaglycerin Monostearate 3 10% aqueous solution of Palmaria extract 1 one Glycerol 10 AT Phenoxyethanol 0.5 Water 82.5 Total one hundred

Table 11 Liquid vesicular dispersions Ingredients Property 31 "Ceramide I" Vesicular dispersed system 32 Ceramide III Vesicular dispersed system 33 Ceramide IIIA Vesicular dispersed system 34 Ceramide IIIB Vesicular dispersed system 35 Ceramide IV Vesicular dispersed system

Example 8

Milk fluid was obtained, which is a drug for external use on the skin in accordance with the following composition. Each of the ingredients (A) were mixed with each other and the mixture was heated to 80 ° C. On the other hand, each of the ingredients (B) was heated to 80 ° C. The mixture of ingredients (B) was added to the mixture of ingredients (A) and mixed to obtain an emulsion. Moreover, ingredients (C) were added there to neutralize the mixture, and after that the mixture was mixed and cooled to 35 ° C in order to obtain milk fluids. Each of the milk fluids maintained a vesicular disperse system after storage for a month at 5 ° C, 20 ° C, or 40 ° C.

Table 12 Ingredients mass% (BUT) Behenyl alcohol 0.5 Cetyl isocyanate 2.0 Squalane 8.0 Dimethicone 2.0 Sorbitan sesquioleate 1,5 POE (45) stearic acid 1,0 Cetyl stearate 0.5 Behenic Acid 0.5 (AT) 1,3-butanediol 5,0 Glycerol 5,0 1,2-octanediol 1,0 Purified water 35.5 The ingredients shown in table 13 fifteen Potassium glycyrrhizinate double 0.1 (FROM) Purified water 21.8 Potassium hydroxide 0.6 Total one hundred

Table 13 Samples Ingredients Milk Liquid 1 Vesicular Dispersion System 1 Milk Liquid 2 Vesicular Dispersion System 2 Milk Liquid 3 Dispersed vesicular system 3 Milk Fluid 4 Vesicular Dispersion System 4 Milk Fluid 5 Vesicular Dispersion System 5 Milk Fluid 6 Vesicular Dispersion System 6 Milk Liquid 7 Vesicular Dispersion System 7 Milk Fluid 8 Vesicular Disperse System 8 Milk Liquid 9 Vesicular Dispersion System 9 Milk Liquid 10 Vesicular Dispersion System 10 Milk Liquid 11 Vesicular Dispersion System 11 Milk Liquid 12 Vesicular Disperse System 12 Milk Liquid 13 Vesicular Dispersion System 13 Milk Liquid 14 Vesicular Disperse System 14 Milk Liquid 15 Vesicular Dispersion System 15 Milk Liquid 16 Vesicular Disperse System 16 Milk Liquid 17 Vesicular Disperse System 17 Milk fluid 18 Dispersed vesicular system 18 Milk Liquid 19 Dispersed vesicular system 19 Milk Liquid 20 Vesicular Dispersion System 20 Milk Liquid 21 Vesicular Dispersion System 21 Milk Liquid 22 Vesicular Dispersion System 22 Milk Liquid 23 Vesicular Dispersion System 23 Milk Liquid 24 Vesicular Disperse System 24 Milk Liquid 25 Vesicular Disperse System 25 Milk Liquid 26 Vesicular Dispersion System 26 Milk Liquid 27 Vesicular Dispersion System 27 Milk fluid 28 Vesicular Dispersion System 28 Milk Liquid 29 Vesicular Dispersion System 29 Milk fluid 30 Vesicular Dispersion System 30 Milk Liquid 31 Vesicular Dispersion System 31 Milk Liquid 32 Vesicular Disperse System 32 Milk Liquid 33 Vesicular Disperse System 33 Milk fluid 34 Vesicular Disperse System 34 Milk Liquid 35 Vesicular Disperse System 35

Industrial applicability

In accordance with the present invention, a method can be implemented that allows the active ingredient to reach the dermis to improve or maintain the skin environment.

The present invention can be used as a medicine for external use on the skin.

Claims (6)

1. A vesicle for application to the skin, including:
1) from 1 to 50 wt.% Α, ε-bis (γ- (C _10-30 ) acylglutamyl) lysine and / or its salt;
2) from 1 to 50 wt.% Ceramide and / or its derivative; and
3) from 5 to 30% by weight of one or more esters selected from a glycerol fatty acid ester, a polyglycerol fatty acid ester and a pyroglutamic acid glycerol ester. 2. The vesicle according to claim 1, in which the acyl group of α, ε-bis (γ-N- (C _10-30 ) acylglutamyl) lysine is a lauroyl group. 3. The vesicle according to claim 1, in which the ceramide or its derivative is a type 2 ceramide or type 3 ceramide. 4. The vesicle according to claim 1, in which one or more esters is selected from glycerol fatty acid ester, polyglycerol fatty acid ester and pyroglutamic acid glycerol ester, and pyroglutamic acid glycerol ester is one or more esters selected from diglycerol monooleate, monoisostearate deca decaglycerol pentaoleate and decaglycerol pentaisostearate. 5. The vesicle according to claim 1, additionally comprising from 0.1 to 30 wt.% One or more of the following active agents to improve or maintain skin: Coptis extract (Ranunculaceae); Citrus aurantium extract (Rutaceae); red algae extract; Houttuynia extract (Saururaceae); Rosmarinus office-nalis extract (Lamiaceae); Betula alba extract (Betulaceae); Achillea extract (Asteraceae); Syzygium aromaticum extract (Myrtaceae); Centella extract (Umbelliferae); Engelhardtia chrysolepis extract (Juglandaceae); Ophiopogon extract (Liliaceae); natural protein hydrolyzate or its acylated product; oleanolic acid or its derivative; betullin; betullic acid or its derivative; panthein sulfonate or its derivative; glycerritic acid or its derivative; hydroquinone or its glycoside; esculin; esculletin; glabridin; methoxysalicylic acid; tranexamic acid or their derivatives; ascorbic acid or its derivatives; L-carnitine. 6. A drug for external application to the skin, comprising from 0.1 to 10 wt.% Vesicles in accordance with any one of claims 1 to 5.